LXR and PPARgamma mediated Abeta clearance mechanisms

描述（由申请人提供）：本申请专注于开发针对阿尔茨海默病（AD）的新治疗方法，其靶向核受体、肝X受体（LXR）和过氧化物酶体增殖物激活受体γ（PPARy）。我们证明了用LXR激动剂治疗AD（Tg2576）的老年动物模型导致A肽水平和斑块负荷的降低。我们发现LXR激动剂从大脑中清除A？的能力依赖于ApoE。重要的是，我们证明了一个全新的机制，通过ApoE促进A肽的蛋白水解降解。LXR激活导致ApoE和脂质转运蛋白ABCA 1的转录诱导。ABCA 1是ApoE通过其脂质化功能成熟所必需的，导致形成含ApoE的HDL样颗粒，其是脑中胆固醇和磷脂运输所必需的。A以高亲和力与ApoE结合，这种相互作用受ApoE的脂化状态控制。我们发现脂化形式的ApoE通过脑啡肽酶依赖的蛋白水解促进小胶质细胞对A肽的细胞内降解。此外，我们证明了脂化的ApoE的行为，伴侣的细胞外降解的胰岛素降解酶的A？。相反，脂化差的ApoE形式形成稳定的蛋白酶抗性复合物。重要的是，相关核受体PPARy的激动剂可以引起类似的作用，我们假设PPARy与LXR参与了一个积极的、自我增强的反馈回路，以刺激ApoE脂质化和A？清除。这些数据建立了一个以前未被认识的ApoE的作用，促进A？从脑中的蛋白水解清除，这可能是其参与AD发病机制的基础。我们建议在AD动物模型中建立LXR激动剂治疗的治疗参数，以预防和逆转AD相关斑块病理学的发展。我们将通过检查LXR已被遗传灭活的AD小鼠模型来验证LXR作为治疗靶点。我们将建立LXR和PPARy靶向基因的机制，最突出的是ApoE和ABCA 1，以促进A？清除。我们将测试PPARy对A ²清除的作用是否是次要的，并依赖于LXR功能。

DESCRIPTION (provided by applicant): This application is focused on the development of new therapeutic approaches to Alzheimer's disease (AD) that target the nuclear receptors, liver X receptors (LXRs) and peroxisome proliferator-activated receptor gamma (PPARy). We demonstrate that treatment of an aged animal model of AD (Tg2576) with LXR agonists results in the reduction of A¿ peptide levels and plaque load. We show that the ability of LXR agonists to clear A¿ from the brain is reliant upon ApoE. Importantly, we demonstrate an entirely novel mechanism through which ApoE facilitates the proteolytic degradation of A¿ peptides. LXR activation results in the transcriptional induction of ApoE and the lipid transporter ABCA1. ABCA1 is required for the functional maturation of ApoE through its lipidation, leading to the formation of ApoE-containing HDL-like particles that are required for cholesterol and phospholipid trafficking in the brain. A¿ binds to ApoE with high affinity and this interaction is governed by the lipidation status of ApoE. We show that lipidated forms of ApoE facilitate the intracellular degradation of A¿ peptides by microglia through neprilysin- dependent proteolysis. Further, we demonstrate that the lipidated ApoE acts to chaperone the extracellular degradation of A¿ by insulin degrading enzyme. In contrast, poorly lipidated forms of ApoE form stable, protease resistant complexes. Importantly, agonists of the related nuclear receptor PPARy can elicit similar effects and we hypothesize that PPARy participates in a positive, self reinforcing, feed back loop with LXR to stimulate ApoE lipidation and A¿ clearance. These data establish a previously unrecognized action of ApoE, facilitating the proteolytic clearance of A¿ from the brain that may underlie its participation in AD pathogenesis. We propose to establish the therapeutic parameters for LXR agonist treatment to prevent and to reverse the development of AD-related plaque pathology in an animal model of AD. We will validate the LXRs as a therapeutic target by examination of murine models of AD in which LXRs have been genetically inactivated. We will establish the mechanisms through which the LXRs and PPARy target genes, most prominently ApoE and ABCA1, to facilitate A¿ clearance. We will test if the actions of PPARy on A¿ clearance are secondary to, and reliant upon, LXR function.